The subject of the appropriate use of the antimicrobial agent for infectious diseases was injectable antimicrobial agent in the hospital until now. Movement to correct inappropriate use of the oral antimicrobial agent in the outpatient became active since national action plan on antimicrobial resistance was published in 2016 by Cabinet Office. For the case that a virus disease was assumed, the number of the prescription of the unnecessary antimicrobial agent in this way decreased. Coming infectious disease treatment changes, and opportunities of the primary care with the self-medication will increase. Most of general commercial drugs are symptomatic treatment medicine for fever, headache, and/or sore throat. In addition, the probiotics including lactic acid bacteria or butyric acid bacteria for the purpose of the improvement of diarrhea symptom is used, too. Furthermore, the biogenics which prevented the infection due to various virus diseases including influenza, and reduced a symptom was released. Though the effect of treatment of infectious diseases by probiotics or biogenics is not shown, as the new infectious disease prevention that a citizen works on, those are expected.

Antimicrobial susceptibility testing has been conducted continuously as post-marketing surveillance of levofloxacin (LVFX) since 1994. The present survey was undertaken to investigate in vitro susceptibilities of bacteria to 33 selected antibacterial agents, focusing on fluoroquinolones (FQs), using 11,705 clinical isolates for 27 species collected from 65 centers during 2016 in Japan.

The common respiratory pathogens of Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, and Haemophilus influenzae continue to show a high susceptibility to FQs, especially to sitafloxacin (STFX), with the susceptibility percentage over 99.8%. On the other hand, the percentage of macrolide-resistant S. pneumoniae and S. pyogenes have increased to 72.9–77.3% and 30.6–32.5% respectively. The isolation frequency of β-lactamase-negative ampicillin-resistant H. influenzae was high at 55.9%, but no increase was observed from 2010. Most strains of Enterobacteriaceae showed a high susceptibility to FQs, but the isolation frequency of STFX-resistant and levofloxacin (LVFX)-resistant Escherichia coli including intermediate resistant strains was 12.7% and 34.2% respectively, and LVFX-resistant rate showed a continuous increase. Another Enterobacteriaceae member, Klebsiella spp., showed low resistance to FQs, in contrast with E. coli, with a susceptibility of over 94.3%. Regarding methicillin-resistant Staphylococcus aureus (MRSA), the percentage of FQ-susceptible isolates were low at 14.6–17.7%, with the exception of 69.3% susceptibility to STFX. On the other hand, methicillin-susceptible S. aureus (MSSA) isolates showed high susceptibility to FQs, at 83.0–99.1%. The susceptibility rate of Enterococcus faecalis and Enterococcus faecium to FQs was 82.4–92.4% and 8.0–21.6% respectively. The percentage of FQ-susceptible Pseudomonas aeruginosa was 91.2–94.2% among isolates derived from urinary tract infections (UTIs), while that from respiratory tract infections (RTIs) was 90.1–94.6%. This was summarized as susceptibility to FQs over 90% in both infections and a continuous decrease in FQ-resistant P. aeruginosa was noted, especially among isolates from UTIs. Regarding multidrug-resistant P. aeruginosa, the isolation frequency was 0.8% from UTIs and 0.5% from RTIs in this survey. Acinetobacter spp. showed high susceptibility to FQs with a susceptibility percentage of 88.4–93.8%. The percentage of imipenem-resistant Acinetobacter spp. was 3.3% (15 isolates) and no multidrug-resistant strain was observed. In Neisseria gonorrhoeae, ceftriaxone (CTRX) showed 100% susceptibility, while CTRX-resistant strains have been detected in both 2010 and 2013 in this survey. MIC₉₀ of STFX was 0.5–4 μg/mL against anaerobes, which were tested for the first time in this survey, but the other FQs showed relatively weak antibacterial activity.

In conclusion, the resistant percentage of methicillin-resistant staphylococci, E. faecium and E. coli to four FQs (LVFX, ciprofloxacin (CPFX), tosufloxacin (TFLX), and pazufloxacin (PZFX)), which have been used clinically for over 15 years, was shown to be 33.2–89.3% in this surveillance, but the results were similar to those from previous surveillance and no significant increase in resistance was observed. On the other hand, the resistant percentage of N. gonorrhoeae to LVFX, CPFX and TFLX was 100%, showing an increase from 74.1% in 2013. Regarding the other bacterial species, the susceptibility rate of S. pyogenes to PZFX and of Proteus mirabilis to CPFX and TFLX was less than 80%, while susceptibility rate to other FQs was maintained at a high level of 80% or more. STFX, which has been on the market since 2008, showed a susceptibility rate of 87.3% or more except for MRSA and E. coli.

Tazobactam/piperacillin (Zosyn^TM), it was approved sepsis, pneumonia, pyelonephritis and complicated cystitis as the indications in July, 2008. Post-marketing surveillance of this agent was conducted to evaluate safety and efficacy between January 2009 and March 2013. For this surveillance of safety and efficacy, 537 and 458 pediatric patients were analyzed respectively from 544 patients enrolled in 87 study sites of the whole country.

The adverse drug reaction was reported in 88 (100 events) of 537 safety analyzed patients, and its incidence rate was 16.4%, including diarrhea (11.7%), liver function abnormal (1.3%), rash(1.3%) and liver disorder(0.7%). Five serious adverse drug reactions were reported in 4 patients, including liver function abnormal, diarrhea, fever and rash. All these serious adverse reactions were recovered or relieved.

The adverse drug reactions specifically reported in pediatric patients were not detected when compared with those in adult patients, however, the rate of the diarrhea was moderately higher in pediatric patients. Furthermore, it was found that the incident rate in patients under 2 years old was moderately higher in that of 2 years or older. It is considered that the attention to awake the incidence of diarrhea in patients under 2 years old should be continued.

The response rate in 458 efficacy evaluable patients was 93.0%. The response rates by the infections were 96.9% in pneumonia, 97.7% in pyelonephritis, 100.0% in complicated cystitis and 74.4% in sepsis, respectively.

From these observations, there was not an unknown event which requires awakening attentions. Zosyn^TM is expected as a useful empiric therapeutic antimicrobial agent for the treatment of various infectious diseases as in the practical guidelines.

Technologies and knowledge in the production and quality control of penicillin (PC) and streptomycin( SM) had been introduced from the USA into Japan under the plan of Dr. Crawford F. Sams, Brigadier General and the chief of the Public Health and Welfare of the Supreme Commander for Allied Powers/General Headquarters.

In 1949, Dr. Sams encouraged the Japanese Ministry of Welfare (JMW) to import newly developed Chloromycetin( CM) from the USA, as the third antibiotic drug in Japan, with the aim to control legally designated infectious diseases (LDID) such as dysentery, typhoid fever, and typhus for which PC and SM were ineffective.

At around the same time, another antibiotic drug, Aureomycin (AM), was scheduled to be imported on a commercial basis. Therefore, the JMW established a special committee to investigate the clinical applications of both CM and AM with the hope of eventually promoting effective domestic utilization.

Owing to the development of adequate clinical applications of CM and AM, public health greatly improved with the successful control of LDID. Subsequently Terramycin and tetracycline (TC), belonging to the same class of AM, and erythromycin of the macrolide (ML) class were introduced from the USA. As a result, a variety of infectious diseases came under effective control.

Some attempts to produce CM and AM at an industrial scale under Japanese original processes were carried out. However, due to limitations placed by patented processes, domestic production was eventually abandoned. Consequently, supplies of these antibiotic drugs depended on the import of pharmaceutical preparations. Preparations were sourced from the USA where some Japanese companies had entered business collaborations with American/European companies, as well as some foreign-affiliated corporations established in Japan. The quality of these imported preparations was controlled via a national certification program conducted by the National Institute of Health Japan under the “Minimum Requirements of Antibiotic Products” enacted in March of 1952.

On the other hand, some antibiotic drugs created in Japan, such as colistin of the peptide class and leucomycin of the ML class, were introduced into clinical use within a short period of time due to evaluations by doctors affiliated with the Japanese Society of Chemotherapy established in 1953.

Thanks to the clinical applications of a variety of antibiotic drugs, people obtained relief from quondam life-threatening infectious diseases (e.g., pneumonia, septicemia, tetanus, tuberculosis, dysentery and typhoid fever) and the benefits from antibiotic use extolled with regard to their extension of average lifespans. Unfortunately, the problem of antibiotic-resistance became more serious in association with the frequent use of antibiotic drugs.

Kanamycin(KM), discovered in 1957 in Japan, showed significant efficacy against difficultto-treat infections caused by PC-resistant Staphylococcus aureus, SM-resistant Mycobacterium tuberculosis, CM/TC-resistant Shigella strains and other resistant pathogenic bacteria. Therefore, extraordinarily rapid clinical development was carried out so that KM could be introduced into Japanese clinics in 1958 and eventually in clinics in the USA and Europe in 1959. Following the development of KM, research and development of antibiotic drugs was directed toward other novel drugs effective against resistant infections, with Japan becoming the main focus country involved with the worldwide efforts.

Since 1980s, drug-resistant bacteria have continued to emerge and spread globally, and the antimicrobial resistance (AMR) become significant threat to human and animal health, food safety, and global security and economy. AMR reduced the effectiveness of treatment for infectious diseases by existing antimicrobials and will represent a step backward in modern medicine to the pre-antibiotic era.

New antimicrobial agents against AMR pathogens are urgently needed, however, current development pipeline is weak and not enough to keep up with pace of emergence of resistance. Over the past two decade, many pharmaceutical companies withdrew from antimicrobial R&D due to scientific challenges (hard to discovery of new class agents and new targets), clinical and regulatory challenges (hard to clinical trial enrollment and high cost for clinical development), and economic challenges (low return to investment). To overcome these challenges, several push and pull incentives are currently working on supporting drug-discovery researches against AMR, reducing clinical and regulatory burden, and extending market exclusivity in USA and Europe. These innovative incentives will become important strategy to stimulate antimicrobial R&D

against AMR infections globally.